DESCRIPTION: Myotonic dystrophy (DM) is caused by the expansion of a CTG repeat. The repeat is in the 3' end of the dystrophia myotonia protein kinase gene (DMPK) and immediately 5" of the dystrophia myotonia associated homeobox protein (DMAHP) gene. It is still unknown whether the altered expression of either of these genes contributes to the DM phenotype. While a large amount of work from other labs has demonstrated that the CTG expansion affects the processing of the DMPK transcript, work in my lab has demonstrated that expression of the adjacent DMAHP gene is suppressed by the expanded repeat. Th investigator's have demonstrated that a well-defined hypersensitive site is positioned between the repeat and the promoter of the DMAHP gene. They have shown that the hypersensitive site contains transcriptional enhancer elements and the activity of these elements correlate with expression of the DMAHP gene suggesting that expansion of the repeat both eliminates the hypersensitive sit and suppresses expression of the adjacent DMAHP gene. These data support the broad hypothesis that the hypersensitive site is critical for the normal regulation of gene expression at the myotonic dystrophy locus, and that suppression of factor access to this region contributes to the myotonic dystrophy phenotype. The broad goals of this application are to characterize the regulatory and structural elements at the myotonic dystrophy locus and determine whether they have a role in the pathogenesis of myotonic dystrophy. The specific aims of the application are to (1) characterize the regulatory elements of hypersensitive site enhancer and DMAHP promoter; (2) characterize the elements at the locus that establish nucleosome phasing and maintain the hypersensitive site; (3) determine whether inactivation of the DMAHP gene or the hypersensitive site enhancer contributes to the phenotype of myotonic dystrophy. The significance of the proposal is that this application will characterize the elements that regulate gene expression at the myotonic dystophy locus and determine the role of these elements in the pathophysiology of myotonic dystrophy, ultimately leading to the rational design of therapies.